JP2016535033A5

JP2016535033A5 -

Info

Publication number: JP2016535033A5
Application number: JP2016526839A
Authority: JP
Filing date: 2014-11-03
Publication date: 2018-02-08

Claims

A method of forming a product represented by R ¹ R ² CH—Ar, comprising:
A combination of a secondary boronic acid represented by R ¹ R ² CH—B (OH) ₂ , an aryl halide represented by Ar—X, a Pd catalyst, a ligand, and Ag ₂ O:

[In the formula, independently for each occurrence,
R ¹ and R ² are selected from the group consisting of substituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ alkyl; or R ¹ and R ² together with the carbon to which they are attached are substituted Or form an unsubstituted C ₃ -C ₈ cycloalkyl;
Ar represents substituted or unsubstituted monocyclic or polycyclic aryl;
X represents halogen;
The Pd catalyst represents Pd (0) or Pd (II);
The ligand represents P (o-R-phenyl) ₃ ;
R represents C ₁ -C ₄ alkyl]
Thereby forming a product represented by R ¹ R ² CH—Ar,
A method comprising:

The process of claim 1, wherein the Pd catalyst represents Pd (0).

The process according to claim 1, wherein the Pd catalyst represents Pd (II).

The method of claim 1, wherein the ligand is P (o-tol) ₃ .

The method according to any one of claims 1 to 4, wherein the secondary boronic acid is achiral.

The method according to any one of claims 1 to 4, wherein the secondary boronic acid is chiral.

The method of claim 6, wherein the secondary boronic acid is a racemic mixture.

The method of claim 6 wherein the secondary boronic acid is not a racemic mixture.

The process of claim 6 wherein the product represented by R ¹ R ² CH-Ar is not a racemic mixture.

R ¹ and R ² is selected from the group consisting of substituted C ₁ -C ₆ alkyl, and unsubstituted C ₁ -C ₆ alkyl, the method according to any one of claims 1 to 9.

R ¹ and R ² together with the carbon to which they are attached, a substituted or form an unsubstituted C ₃ -C ₈ cycloalkyl, a method according to any one of claims 1-4 and 6-9.

12. A method according to any one of claims 1 to 11 , wherein Ar represents substituted or unsubstituted phenyl.

12. A method according to any one of claims 1 to 11 , wherein Ar represents substituted or unsubstituted polycyclic aryl.

14. A method according to any one of claims 1 to 13 , wherein X is Br.

14. A method according to any one of claims 1 to 13 , wherein X is I.

In the method of forming an air stable chiral secondary boronic acid, the air stable chiral secondary boronic acid is not a racemic mixture,
Formula (I):

Wherein, independently of each occurrence, R ¹ and R ² are selected from the group consisting of substituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ alkyl.
A chiral secondary boronic acid represented by: a chiral iminodiacetic acid that is not a racemic mixture; a weak acid catalyst; and a polar aprotic solvent, thereby forming a mixture of chiral boronates;
Splitting the mixture of chiral boronates into individual diastereomers; and hydrolyzing the individual diastereomers, thereby producing an air-stable chiral secondary boronic acid that is not a racemic mixture. Forming step;
A method comprising:

The method of claim 16 , wherein the dividing is by crystallization.

The method according to claim 16 , wherein the dividing is performed by chromatography.

The method according to any one of claims 16 to 18 , wherein the hydrolyzing step is performed with an aqueous hydroxide solution.

The method according to any one of claims 16 to 18 , wherein the hydrolyzing step is performed with an aqueous NaOH solution.

21. A method according to any one of claims 16 to 20 , wherein the chiral iminodiacetic acid is benzylcyclopentyliminodiacetic acid (BIDA).

The method according to any one of claims 16 to 21 , wherein the weak acid catalyst is pyridinium p-toluenesulfonate (PPTS).

Wherein the polar aprotic solvent is CH ₃ CN, the method according to any one of claims 16 22.

24. A process according to any one of claims 16 to 23 , wherein the chiral secondary boronic acid represented by formula (I) is a racemic mixture.

24. A process according to any one of claims 16 to 23 , wherein the chiral secondary boronic acid represented by formula (I) is not a racemic mixture.

In a method of forming a stable trihydroxyborate salt in air of primary or secondary boronic acid,
(I) Formula (II):

A primary or secondary boronate represented by: a first polar aprotic solvent, and an aqueous hydroxide solution, thereby providing a compound of formula (I):

Forming a primary or secondary boronic acid represented by
In the formula, independently for each occurrence,
R ¹ is selected from the group consisting of substituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ alkyl;
R ² is selected from the group consisting of H, substituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ alkyl;
R ^a and R ^b are selected from the group consisting of optionally substituted alkyl, aryl and acyl; or R ^a and R ^b are —O—B (CHR ¹ R ² ) —O to which they are attached. Together with the moiety -optionally substituted heterocycle, the heterocycle of which is composed of 5-10 heavy atoms, wherein B, O, and A step wherein 3-5 heteroatoms independently selected from the group consisting of N are present in the heterocycle; and (ii) the primary or secondary boronic acid represented by formula (I), Combining ether, and concentrated hydroxide, thereby forming a stable trihydroxyborate salt in air of primary or secondary boronic acid;
A method comprising:

Combining said air-stable trihydroxyborate salt of a primary or secondary boronic acid, a Lewis acid, and a second polar aprotic solvent, thereby providing said first represented by formula (I) 27. The method of claim 26 , further comprising the step of reforming a secondary or secondary boronic acid.

Wherein the Lewis acid is BF ₃ OEt _2, The method of claim 27, wherein.

28. The method of claim 26 or 27 , wherein the second polar aprotic solvent is dioxane.

Said primary or secondary boronate represented by formula (II) is represented by formula (III):

In the formula, independently for each occurrence,
R ¹ is selected from the group consisting of substituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ alkyl;
R ² is selected from the group consisting of H, substituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ alkyl;
B represents boron with sp ³ hybrid orbitals;
^{^{^{R 20, R 21, R 22}}} , R 23, and R ²⁴ are independently selected from the group consisting of hydrogen group and an organic group, the process according to any one of claims 26 29.

^{^{^{R 21, R 22, R 23}}} , and each R ²⁴ represents a hydrogen group, The method of claim 30.

32. A method according to any one of claims 26 to 31 , wherein the primary or secondary boronate represented by formula (II) is achiral.

33. A method according to any one of claims 26 to 32 , wherein the primary or secondary boronic acid represented by formula (I) is a primary boronic acid.

33. A method according to any one of claims 26 to 32 , wherein the primary or secondary boronic acid represented by formula (I) is a secondary boronic acid.

33. The method of any one of claims 26 to 32 , wherein the air-stable salt of the primary or secondary boronic acid is achiral.

32. A method according to any one of claims 26 to 31 wherein the primary or secondary boronate represented by formula (II) is chiral.

Said primary or secondary boronate represented by formula (II) is represented by formula (IV):

37. The method of claim 36 , represented by:

38. A method according to claim 36 or 37 , wherein the primary or secondary boronic acid represented by formula (I) is a primary boronic acid.

38. A method according to claim 36 or 37 , wherein said primary or secondary boronic acid represented by formula (I) is a secondary boronic acid.

40. The method of claim 39 , wherein the secondary boronic acid is achiral.

40. The method of claim 39 , wherein the secondary boronic acid is chiral.

42. The method of claim 41 , wherein the chiral secondary boronic acid represented by formula (I) is a racemic mixture.

42. The method of claim 41 , wherein the chiral secondary boronic acid represented by formula (I) is not a racemic mixture.

44. A method according to any one of claims 36 to 43 , wherein the chiral primary or secondary boronate represented by formula (II) is a racemic mixture.

44. A method according to any one of claims 36 to 43 , wherein said chiral primary or secondary boronate represented by formula (II) is not a racemic mixture.

42. The method of claim 41 , wherein the air-stable salt of the primary or secondary boronic acid is a chiral air-stable salt of the secondary boronic acid.

47. The method of claim 46 , wherein the chiral air stable salt of the secondary boronic acid is a racemic mixture.

47. The method of claim 46 , wherein the chiral air stable salt of the secondary boronic acid is not a racemic mixture.

49. The method of any one of claims 26 to 48 , wherein the first polar aprotic solvent is tetrahydrofuran (THF).

The method according to any one of claims 26 to 49 , wherein the aqueous hydroxide solution is an aqueous NaOH solution.

51. A method according to any one of claims 26 to 50 , wherein the ether is methyl tert-butyl ether (MTBE).

52. A method according to any one of claims 26 to 51 , wherein the concentrated hydroxide is concentrated NaOH.

A method of forming a boronic acid comprising:

[Where:
R ^a represents an organic group,
MIDA represents N-methyliminodiacetic acid]
A method comprising the steps represented by:

54. The method of claim 53 , wherein the weak acid catalyst is pyridinium p-toluenesulfonate (PPTS).

The first polar aprotic solvent is CH ₃ CN, according to claim 53 or 54 A method according.

56. A method according to any one of claims 53 to 55 , wherein the base is NaOH.

57. The method of any one of claims 53 to 56 , wherein the second polar aprotic solvent is tetrahydrofuran (THF).

The organic group is a chiral organic group, and the boronic acid

58. The method of any one of claims 53 to 57 , wherein is a chiral boronic acid.

59. The method of claim 58 , wherein the chiral organic group is a racemic mixture and the chiral boronic acid is a racemic mixture.

59. The method of claim 58 , wherein the chiral organic group is not a racemic mixture and the chiral boronic acid is not a racemic mixture.